The overall objective of this proposal is to study the possibility that in some systemic sclerosis patients, a persistent bacterial infection involving dermal microvascular endothelium or other cells that are resident in skin results in the obliterative microvasculopathy and/or the fibrosing features of this disease. As a first step in addressing this issue, we will test the following hypothesis: persistent bacterial infection of skin or microvasculature occurs more commonly in systemic sclerosis cases than in matched controls and participates in the disease process. Specific aims are: (1) to test skin biopsies from 60 systemic scleroderma patients and 30 matched normal controls for evidence of bacterial persistence by pan-bacterial and chlamydia-specific molecular screening; (2) to microdissect dermal vessels from these same cases and controls and test this tissue by panbacterial and chlamydia-specific molecular probes; (3) to prepare PBMC'S from these individuals and screen with these probes; and (4) depending on positive results, to perform immunohistochemistry studies for these organisms on skin biopsies/vessels from selected patients and appropriate controls. Scleroderma small vessel vasculopathy shares some key features with large vessel atherosclerosis, a condition also characterized by intimal proliferation and luminal narrowing among multiple other abnormalities. Inflammation may play an important role in the pathogenesis of atherosclerosis raising the possibility of infectious agents as mediators in this process. There are several examples of infection resulting in chronic inflammatory autoimmune diseases including Lyme disease (Borrelia burgdorferii), and reactive arthritis (ReA), an inflammatory joint disease associated with prior infection by a number of specific bacterial pathogens, including Chlamydia trachomatis and various species of the Genera Salmonella, Yersinia, Campylobacter, and others. This research team is comprised of individuals with expertise in clinical scleroderma, the vascular abnormalities of primary and secondary Raynaud's disease, and autoimmunity related to persistent bacterial infections with relevant pathogens. If positive results are obtained in at least a subset of scleroderma cases, intervention trials could be devised with therapy targeted to specific organisms.